Browsing by Author "Opoka, Robert O."
Now showing 1 - 10 of 67
Results Per Page
Sort Options
Item Acute kidney injury in hospitalized children with sickle cell anemia(BMC, 2022-03-18) Batte, Anthony; Menon, Sahit; Ssenkusu, John; Kiguli, Sarah; Kalyesubula, Robert; Lubega, Joseph; Mutebi, Edrisa Ibrahim; Opoka, Robert O.; John, Chandy C.; Starr, Michelle C.; Conroy, Andrea L.; Pediatrics, School of MedicineBackground: Children with sickle cell anemia (SCA) are at increased risk of acute kidney injury (AKI) that may lead to death or chronic kidney disease. This study evaluated AKI prevalence and risk factors in children with SCA hospitalized with a vaso-occlusive crisis (VOC) in a low-resource setting. Further, we evaluated whether modifications to the Kidney Disease: Improving Global Outcomes (KDIGO) definition would influence clinical outcomes of AKI in children with SCA hospitalized with a VOC. Methods: We prospectively enrolled 185 children from 2 - 18 years of age with SCA (Hemoglobin SS) hospitalized with a VOC at a tertiary hospital in Uganda. Kidney function was assessed on admission, 24-48 h of hospitalization, and day 7 or discharge. Creatinine was measured enzymatically using an isotype-dilution mass spectrometry traceable method. AKI was defined using the original-KDIGO definition as ≥ 1.5-fold change in creatinine within seven days or an absolute change of ≥ 0.3 mg/dl within 48 h. The SCA modified-KDIGO (sKDIGO) definition excluded children with a 1.5-fold change in creatinine from 0.2 mg/dL to 0.3 mg/dL. Results: Using KDIGO, 90/185 (48.7%) children had AKI with 61/185 (33.0%) AKI cases present on admission, and 29/124 (23.4%) cases of incident AKI. Overall, 23 children with AKI had a 1.5-fold increase in creatinine from 0.2 mg/dL to 0.3 m/dL. Using the sKDIGO-definition, 67/185 (36.2%) children had AKI with 43/185 (23.2%) cases on admission, and 24/142 (16.9%) cases of incident AKI. The sKDIGO definition, but not the original-KDIGO definition, was associated with increased mortality (0.9% vs. 7.5%, p = 0.024). Using logistic regression, AKI risk factors included age (aOR, 1.10, 95% CI 1.10, 1.20), hypovolemia (aOR, 2.98, 95% CI 1.08, 8.23), tender hepatomegaly (aOR, 2.46, 95% CI 1.05, 5.81), and infection (aOR, 2.63, 95% CI 1.19, 5.81) (p < 0.05). Conclusion: These results demonstrate that AKI is a common complication in children with SCA admitted with VOC. The sKDIGO definition of AKI in children with SCA was a better predictor of clinical outcomes in children. There is need for promotion of targeted interventions to ensure early identification and treatment of AKI in children with SCA.Item Acute kidney injury in Ugandan children with severe malaria is associated with long-term behavioral problems(Public Library of Science, 2019-12-17) Hickson, Meredith R.; Conroy, Andrea L.; Bangirana, Paul; Opoka, Robert O.; Idro, Richard; Ssenkusu, John M.; John, Chandy C.; Pediatrics, School of MedicineBackground Acute kidney injury (AKI) is a risk factor for neurocognitive impairment in severe malaria (SM), but the impact of AKI on long-term behavioral outcomes following SM is unknown. Methods We conducted a prospective study on behavioral outcomes of Ugandan children 1.5 to 12 years of age with two forms of severe malaria, cerebral malaria (CM, n = 226) or severe malarial anemia (SMA, n = 214), and healthy community children (CC, n = 173). AKI was defined as a 50% increase in creatinine from estimated baseline. Behavior and executive function were assessed at baseline and 6, 12, and 24 months later using the Child Behavior Checklist and Behavior Rating Inventory of Executive Function, respectively. Age-adjusted z-scores were computed for each domain based on CC scores. The association between AKI and behavioral outcomes was evaluated across all time points using linear mixed effect models, adjusting for sociodemographic variables and disease severity. Results AKI was present in 33.2% of children with CM or SMA at baseline. Children ≥6 years of age with CM or SMA who had AKI on admission had worse scores in socio-emotional function in externalizing behaviors (Beta (95% CI), 0.52 (0.20, 0.85), p = 0.001), global executive function (0.48 (0.15, 0.82), p = 0.005) and behavioral regulation (0.66 (0.32, 1.01), p = 0.0002) than children without AKI. There were no behavioral differences associated with AKI in children <6 years of age. Conclusions AKI is associated with long-term behavioral problems in children ≥6 years of age with CM or SMA, irrespective of age at study enrollment.Item Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria(Springer Nature, 2019-05-21) Conroy, Andrea L.; Opoka, Robert O.; Bangirana, Paul; Idro, Richard; Ssenkusu, John M.; Datta, Dibyadyuti; Hodges, James S.; Morgan, Catherine; John, Chandy C.; Pediatrics, School of MedicineBACKGROUND: Acute kidney injury (AKI) is a recognized complication of pediatric severe malaria, but its long-term consequences are unknown. METHODS: Ugandan children with cerebral malaria (CM, n = 260) and severe malaria anemia (SMA, n = 219) or community children (CC, n = 173) between 1.5 and 12 years of age were enrolled in a prospective cohort study. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to retrospectively define AKI and chronic kidney disease (CKD). Cognitive testing was conducted using the Mullen Scales of Early Learning in children < 5 and Kaufman Assessment Battery for Children (K-ABC) second edition in children ≥ 5 years of age. RESULTS: The prevalence of AKI was 35.1%, ranging from 25.1% in SMA to 43.5% in CM. In-hospital mortality was 11.9% in AKI compared to 4.2% in children without AKI (p = 0.001), and post-discharge mortality was 4.7% in AKI compared to 1.3% in children without AKI (p = 0.030) corresponding to an all-cause adjusted hazard ratio of 2.30 (95% CI 1.21, 4.35). AKI was a risk factor for short- and long-term neurocognitive impairment. At 1 week post-discharge, the frequency of neurocognitive impairment was 37.3% in AKI compared to 13.5% in children without AKI (adjusted odds ratio (aOR) 2.31 [95% CI 1.32, 4.04]); at 1-year follow-up, it was 13.3% in AKI compared to 3.4% in children without AKI (aOR 2.48 [95% CI 1.01, 6.10]), and at 2-year follow-up, it was 13.0% in AKI compared to 3.4% in children without AKI (aOR 3.03 [95% CI 1.22, 7.58]). AKI was a risk factor for CKD at 1-year follow-up: 7.6% of children with severe malaria-associated AKI had CKD at follow-up compared to 2.8% of children without AKI (p = 0.038) corresponding to an OR of 2.81 (95% CI 1.02, 7.73). The presenting etiology of AKI was consistent with prerenal azotemia, and lactate dehydrogenase as a marker of intravascular hemolysis was an independent risk factor for AKI in CM and SMA (p < 0.0001). In CM, AKI was associated with the presence and severity of retinopathy (p < 0.05) and increased cerebrospinal fluid albumin suggestive of blood-brain barrier disruption. CONCLUSIONS: AKI is a risk factor for long-term neurocognitive impairment and CKD in pediatric severe malaria.Item Acute kidney injury, persistent kidney disease, and post-discharge morbidity and mortality in severe malaria in children: A prospective cohort study(Elsevier, 2022-02-12) Namazzi, Ruth; Batte, Anthony; Opoka, Robert O.; Bangirana, Paul; Schwaderer, Andrew L.; Berrens, Zachary; Datta, Dibyadyuti; Goings, Michael; Ssenkusu, John M.; Goldstein, Stuart L.; John, Chandy C.; Conroy, Andrea L.; Pediatrics, School of MedicineBackground: Globally, 85% of acute kidney injury (AKI) cases occur in low-and-middle-income countries. There is limited information on persistent kidney disease (acute kidney disease [AKD]) following severe malaria-associated AKI. Methods: Between March 28, 2014, and April 18, 2017, 598 children with severe malaria and 118 community children were enrolled in a two-site prospective cohort study in Uganda and followed up for 12 months. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to define AKI (primary exposure) and AKD at 1-month follow-up (primary outcome). Plasma neutrophil gelatinase-associated lipocalin (NGAL) was assessed as a structural biomarker of AKI. Findings: The prevalence of AKI was 45·3% with 21·5% of children having unresolved AKI at 24 h. AKI was more common in Eastern Uganda. In-hospital mortality increased across AKI stages from 1·8% in children without AKI to 26·5% with Stage 3 AKI (p < 0·0001). Children with a high-risk plasma NGAL test were more likely to have unresolved AKI (OR, 7·00 95% CI 4·16 to 11·76) and die in hospital (OR, 6·02 95% CI 2·83 to 12·81). AKD prevalence was 15·6% at 1-month follow-up with most AKD occurring in Eastern Uganda. Risk factors for AKD included severe/unresolved AKI, blackwater fever, and a high-risk NGAL test (adjusted p < 0·05). Paracetamol use during hospitalization was associated with reduced AKD (p < 0·0001). Survivors with AKD post-AKI had higher post-discharge mortality (17·5%) compared with children without AKD (3·7%). Interpretation: Children with severe malaria-associated AKI are at risk of AKD and post-discharge mortality.Item Adherence to clinical guidelines is associated with reduced inpatient mortality among children with severe anemia in Ugandan hospitals(PLOS, 2019-01-25) Opoka, Robert O.; Ssemata, Andrew S.; Oyang, William; Nambuya, Harriet; John, Chandy C.; Karamagi, Charles; Tumwine, James K.; Pediatrics, School of MedicineBACKGROUND: In resource limited settings, there is variability in the level of adherence to clinical guidelines in the inpatient management of children with common conditions like severe anemia. However, there is limited data on the effect of adherence to clinical guidelines on inpatient mortality in children managed for severe anemia. METHODS: We analyzed data from an uncontrolled before and after in-service training intervention to improve quality of care in Lira and Jinja regional referral hospitals in Uganda. Inpatient records of children aged 0 to 5 years managed as cases of 'severe anemia (SA)' were reviewed to ascertain adherence to clinical guidelines and compare inpatient deaths in SA children managed versus those not managed according to clinical guidelines. Logistic regression analysis was conducted to evaluate the relationship between clinical care factors and inpatient deaths amongst patients managed for SA. RESULTS: A total of 1,131 children were assigned a clinical diagnosis of 'severe anemia' in the two hospitals. There was improvement in the level of care after the in-service training intervention with more children being managed according to clinical guidelines compared to the period before, 218/510 (42.7%) vs 158/621 (25.4%) (p < 0.001). Overall, children managed according to clinical guidelines had reduced risk of inpatient mortality compared to those not managed according to clinical guidelines, [OR 0.28, (95%, CI 0.14, 0.55), p = 0.001]. Clinical care factors associated with decreased risk of inpatient death included, having pre-transfusion hemoglobin done to confirm diagnosis [OR 0.5; 95% CI 0.29, 0.87], a co-morbid diagnosis of severe malaria [OR 0.4; 95% CI 0.25, 0.76], and being reviewed after admission by a clinician [OR 0.3; 95% CI 0.18, 0.59], while a co-morbid diagnosis of severe acute malnutrition was associated with increased risk of inpatient death [OR 4.2; 95% CI 2.15, 8.22]. CONCLUSION: Children with suspected SA who are managed according to clinical guidelines have lower in-hospital mortality than those not managed according to the guidelines. Efforts to reduce inpatient mortality in SA children in resource-limited settings should focus on training and supporting health workers to adhere to clinical guidelines.Item Adipose tissue parasite sequestration drives leptin production in mice and correlates with human cerebral malaria(American Association for the Advancement of Science, 2021-03-24) Mejia, Pedro; Treviño-Villarreal, J. Humberto; De Niz, Mariana; Meibalan, Elamaran; Longchamp, Alban; Reynolds, Justin S.; Turnbull, Lindsey B.; Opoka, Robert O.; Roussilhon, Christian; Spielmann, Tobias; Ozaki, C. Keith; Heussler, Volker T.; Seydel, Karl B.; Taylor, Terrie E.; John, Chandy C.; Milner, Danny A.; Marti, Matthias; Mitchell, James R.; Medicine, School of MedicineCirculating levels of the adipokine leptin are linked to neuropathology in experimental cerebral malaria (ECM), but its source and regulation mechanism remain unknown. Here, we show that sequestration of infected red blood cells (iRBCs) in white adipose tissue (WAT) microvasculature increased local vascular permeability and leptin production. Mice infected with parasite strains that fail to sequester in WAT displayed reduced leptin production and protection from ECM. WAT sequestration and leptin induction were lost in CD36KO mice; however, ECM susceptibility revealed sexual dimorphism. Adipocyte leptin was regulated by the mechanistic target of rapamycin complex 1 (mTORC1) and blocked by rapamycin. In humans, although Plasmodium falciparum infection did not increase circulating leptin levels, iRBC sequestration, tissue leptin production, and mTORC1 activity were positively correlated with CM in pediatric postmortem WAT. These data identify WAT sequestration as a trigger for leptin production with potential implications for pathogenesis of malaria infection, prognosis, and treatment.Item Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia(American Medical Association, 2021-12) Datta, Dibyadyuti; Bangirana, Paul; Opoka, Robert O.; Conroy, Andrea L.; Co, Katrina; Bond, Caitlin; Zhao, Yi; Kawata, Keisuke; Saykin, Andrew J.; John, Chandy C.; Biostatistics and Health Data Science, School of MedicineImportance: Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. Objective: To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. Design, setting, and participants: This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. Exposure: CM or SMA. Main outcomes and measures: Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. Results: A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (β = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (β = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (β = -1.39; 95% CI, -2.18 to -0.60; P = .001). Conclusions and relevance: In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.Item Autoantibody levels are associated with acute kidney injury, anemia and post-discharge morbidity and mortality in Ugandan children with severe malaria(Nature Research, 2019-10-17) Rivera-Correa, Juan; Conroy, Andrea L.; Opoka, Robert O.; Batte, Anthony; Namazzi, Ruth; Ouma, Benson; Bangirana, Paul; Idro, Richard; Schwaderer, Andrew L.; John, Chandy C.; Rodriguez, Ana; Pediatrics, School of MedicineAutoantibodies targeting host antigens contribute to autoimmune disorders, frequently occur during and after infections and have been proposed to contribute to malaria-induced anemia. We measured anti-phosphatidylserine (PS) and anti-DNA antibody levels in 382 Ugandan children prospectively recruited in a study of severe malaria (SM). High antibody levels were defined as antibody levels greater than the mean plus 3 standard deviations of community children (CC). We observed increases in median levels of anti-PS and anti-DNA antibodies in children with SM compared to CC (p < 0.0001 for both). Children with severe malarial anemia were more likely to have high anti-PS antibodies than children with cerebral malaria (16.4% vs. 7.4%), p = 0.02. Increases in anti-PS and anti-DNA antibodies were associated with decreased hemoglobin (p < 0.05). A one-unit increase in anti-DNA antibodies was associated with a 2.99 (95% CI, 1.68, 5.31) increase odds of acute kidney injury (AKI) (p < 0.0001). Elevated anti-PS and anti-DNA antibodies were associated with post-discharge mortality (p = 0.031 and p = 0.042, respectively). Children with high anti-PS antibodies were more likely to have multiple hospital readmissions compared to children with normal anti-PS antibody levels (p < 0.05). SM is associated with increased autoantibodies against PS and DNA. Autoantibodies were associated with anemia, AKI, post-discharge mortality, and hospital readmission.Item Biomarkers of Systemic Inflammation in Ugandan Infants and Children Hospitalized With Respiratory Syncytial Virus Infection(Wolters Kluwer, 2019-08) Sawatzky, Julia; Soo, Jeremy; Conroy, Andrea L.; Bhargava, Ravi; Namasopo, Sophie; Opoka, Robert O.; Hawkes, Michael T.; Pediatrics, School of MedicineBackground: Optimizing outcomes in respiratory syncytial virus (RSV) pneumonia requires accurate diagnosis and determination of severity that, in resource-limited settings, is often based on clinical assessment alone. We describe host inflammatory biomarkers and clinical outcomes among children hospitalized with RSV lower respiratory tract infection (LRTI) in Uganda and controls with rhinovirus and pneumococcal pneumonia. Methods: 58 children hospitalized with LRTI were included. We compared 37 patients with RSV, 10 control patients with rhinovirus and 11 control patients with suspected pneumococcal pneumonia. Results: Patients in the RSV group had significantly lower levels of C-reactive protein (CRP) and chitinase-3-like protein 1 (CHI3L1) than the pneumococcal pneumonia group (P < 0.05 for both). Among children with RSV, higher admission levels of CRP predicted prolonged time to resolution of tachypnea, tachycardia and fever. Higher levels of CHI3L1 were associated with higher composite clinical severity scores and predicted prolonged time to resolution of tachypnea and tachycardia, time to wean oxygen and time to sit. Higher levels of lipocalin-2 (LCN2) predicted prolonged time to resolution of tachypnea, tachycardia and time to feed. Higher admission levels of all 3 biomarkers were predictive of a higher total volume of oxygen administered during hospitalization (P < 0.05 for all comparisons). Of note, CHI3L1 and LCN2 appeared to predict clinical outcomes more accurately than CRP, the inflammatory biomarker most widely used in clinical practice. Conclusions: Our findings suggest that CHI3L1 and LCN2 may be clinically informative biomarkers in childhood RSV LRTI in low-resource settings.Item Blackwater fever and acute kidney injury in children hospitalized with an acute febrile illness: pathophysiology and prognostic significance(BMC, 2022-07-01) Conroy, Andrea L.; Hawkes, Michael T.; Leligdowicz, Aleksandra; Mufumba, Ivan; Starr, Michelle C.; Zhong, Kathleen; Namasopo, Sophie; John, Chandy C.; Opoka, Robert O.; Kain, Kevin C.; Pediatrics, School of MedicineBackground: Acute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood. Methods: A prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression. Results: We evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity. Conclusions: BWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures.